rs1555440081
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The ENST00000288840.10(SMAD6):āc.1102C>Gā(p.Leu368Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L368P) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000288840.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.1102C>G | p.Leu368Val | missense_variant | 4/4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | XM_011521561.3 | c.319C>G | p.Leu107Val | missense_variant | 4/4 | XP_011519863.1 | ||
SMAD6 | NR_027654.2 | n.2257C>G | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.1102C>G | p.Leu368Val | missense_variant | 4/4 | 1 | NM_005585.5 | ENSP00000288840 | P1 | |
SMAD6 | ENST00000557916.5 | c.*217C>G | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 1 | ENSP00000452955 | ||||
SMAD6 | ENST00000559931.5 | c.*217C>G | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 3 | ENSP00000453446 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456018Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 724702
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2022 | The p.L368V variant (also known as c.1102C>G), located in coding exon 4 of the SMAD6 gene, results from a C to G substitution at nucleotide position 1102. The leucine at codon 368 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD6 protein function. ClinVar contains an entry for this variant (Variation ID: 471744). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the SMAD6 protein (p.Leu368Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at